Pharmaceutical composition based on ketorolac or one of its salts pharmaceutically acceptable and use of ketorolac or its salts in pharmaceutical compositions

ABSTRACT

The present invention refers to pharmaceutical compositions based on ketorolac or one of its salts pharmaceutically acceptable, as well as the use of ketorolac or one of its salts acceptable from pharmaceutical viewpoint, for preparation of a pharmaceutical composition (tablets) for sublingual administration, with the purpose of accelerating the pharmacological response to ketorolac, without making use of the injectable via. On the other hand, a pharmaceutical composition is described encompassing, as one of its active principles, ketorolac or one of its salts acceptable from pharmaceutical viewpoint, representing from 10 to 15% by weight, in relation to the total weight of the compound and as the essential excipient, a ternary mixture of lactose/sorbitol/cellulose, eventually in a mixture with other excipients acceptable from pharmaceutical viewpoint.

FIELD OF THE INVENTION

The present invention refers to the use of ketorolac or one of itssalts, acceptable from pharmaceutical point of view, for preparation ofa pharmaceutical composition in tablets, for sublingual administration,to accelerate the pharmaceutical response, especially the analgesicresponse by the use of ketorolac.

STATE OF THE ART

Ketorolac is a medicament inhibitor of prostaglandin synthesis, whichformula is

notably known by its anti-inflammatory, analgesic and antipyretic actionas described in Patent U.S. Pat. No. 4,089,969, in which tromethamolsalt is used in its racemic form.

Pharmaceutical formulations with analgesic and antipyretic action,containing R form, were also described in the state of the art, as canbe noted in the patent document EP 674511. It should also be emphasizedthat ketorolac may be used for the therapy in periodontal affectiontreatments, as described in patent document WO 91/13609, and for thetreatment of carcinomas of the scaly cells in the oral cavity or of theoropharynx, as taught in the patent document WO 96/28144.

In the several indications mentioned in the literature, ketorolac wasproposed using several administration routes. For example, Patent U.S.Pat. No. 4,089,969 suggests the oral, parenteral or topicadministration, in several pharmaceutical forms, particularly intablets, suppository, pills, capsules, powder, solutions, suspensions,emulsions, creams, lotions and unguents.

However, patent document WO 91/13609 suggests the application ofketorolac through dentifrices, solutions for mouthwash, spray for oralcavity or dental solutions. The latter type of ketorolac application isalso suggested in patent document WO 96/28144.

The Patent U.S. Pat. No. 6,090,368 describes the nasal spray, whereaspatent document WO 99/09954 describes a compound for skin topicadministration and patent document EP 668759 describes ketorolacadministration by transdermic via.

Currently, ketorolac, in the form of tromethanol salt is used by oralvia in tablets of 10 mg or dropwise, in a solution of 2%, by injectablevia, being provided in flasks of 10 or 30 mg, and by rectal via insuppositories of 30 mg.

Consequently, in order to obtain a rapid anti-inflammatory, antipyreticand analgesic action of ketorolac, the single current possibility is tomake use of the injectable administration via, which knowingly causesslight illness and discomfort to the patient. Particularly due to itsuse as analgesic, a greater speed of ketorolac action assumes asignificant importance.

SUMMARY OF THE INVENTION

It was recently proved that with ketorolac administration or one of itssalts acceptable from pharmaceutical viewpoint, more particularly itstromethamol salt by sublingual via, the absorption of the activeprinciple is more rapidly obtained than in comparison with the oraladministration, thus resulting in a more rapid therapeutic action withplasmatic levels of the active principle equal or very close to thoseobtained after the traditional oral administration, which results in atherapeutic activity very close, if not equal to the previous one, oreven better.

On the other hand, it was proved that a pharmaceutical, compositioncomposed by the essential carrier containing 10-15% in weight ofketorolac or one of its salts acceptable from pharmaceutical point ofview, preferably tromethamol ketorolac, and with at least 60% of thetotal weight of the compound represented by essential excipients,composed by ternary mixture of lactose/sorbitol/cellulose in therespective weight percentages (in relation to the total weight of thecompound) of 30-50%/3-9%/9-17%, is rapidly absorbed by sublingual via,allowing to achieve the hematic levels of ketorolac rapidly, withsufficient value to assure the therapeutic activity desired in the abovementioned indications, particularly in relation to the analgesicproperty.

The term “essential carrier” refers to the pharmaceutical compositioncontaining a mixture of the active principle of ketorolac compound orone of its salts acceptable from pharmaceutical viewpoint, particularlyits tromethamol salt, an excipient necessary to compose the formulation,which is presented in the form of sublingual tablets for oraladministration, specially including the essential excipients. The term“essential excipients” refers to the mixture of the excipients or theternary mixture lactose/sorbitol/cellulose in specific proportions(lactose (30-50% in weight)/sorbitol (3-9% in weight)/cellulose (9-17%in weight). The term “ternary mixture” refers to the three excipients,lactose/sorbitol/cellulose. Hereinafter, the terms essential carrier,essential excipients and ternary mixture will appear in the presentdocument meaning the foregoing explanation.

The term “ketorolac” represents the International Common Denomination”(DCI) of the racemic form of5-benzyl-2,3-dihydro-1H-pyrrolizin-1-carboxylic acid.

The term “tromethamol” represents the DCI of2-amino-2-(hydroxymethyl)-1,3-propanediol, also indicated as“tromethamine” in USP dictionary of pharmaceutical products.

The expression “tromethamol ketorolac”, specifically designates thetromethamol ketorolac salt.

DETAILED DESCRIPTION OF THE INVENTION

According to one of its aspects, the present invention refers to the useof ketorolac or one of its salts acceptable from pharmaceuticalviewpoint, for the preparation of a pharmaceutical composition forsublingual administration destined to accelerate the pharmacologicalresponse to ketorolac without making use of the injectable via. It isunderstood by the term “sublingual”, the application of the activeprinciple through the administration of the pharmaceutical compositionin the said sublingual form, i.e., under the tongue or gingiva, i.e.,placing the tablet between the cheek and the gingiva.

It is understood that the expression “pharmacological response toketorolac” refers to the response due to the systemic action ofketorolac itself or one of its salts acceptable from pharmaceuticalviewpoint, preferably the tromethamol salt, in the treatment of theaforementioned diseases.

One of the advantageous uses of ketorolac or one of its salts acceptablefrom pharmaceutical viewpoint, consists of the preparation of apharmaceutical composition for sublingual administration with thepurpose of accelerating the analgesic response of ketorolac withoutmaking use of the injectable via. Even more advantageous, the inventionrefers to the use of tromethamol ketorolac for preparation of thepharmaceutical compounds for sublingual administration destined toaccelerate the analgesic response of ketorolac without making use of theinjectable via.

According to one of its other aspects, the present invention provides apharmaceutical composition for sublingual use, due to the quality of oneof its principle actives, reaching from 10 to 15% in weight of ketorolacor one of its salts acceptable from pharmaceutical viewpoint, mixed witha pharmaceutical excipient formed by, at least, 60% in relation to thetotal weight of the excipients of a diluent composed of a polyalcoholderivative from reduction of a monosaccharide and a carbohydrate, atleast.

In the present context, unless otherwise indicated, the specificindication of the percentages is given in weight and refers to the totalweight of the composition.

The referred pharmaceutical composition may promote the acceleration ofketorolac pharmacological response. It is composed of tablets forsublingual administration containing from 2 to 15 mg of ketorolac or oneof its salts acceptable from pharmaceutical viewpoint.

The same is particularly destined to the rapid induction of theanalgesia in patients requiring this rapid induction.

The recommended dosage unit of the referred to agonists is composed of2.5; 5 or 10 mg of ketorolac, preferably tromethamol ketorolac mixedwith excipients, of which, at least, 60% is composed of a polyalcoholderivative of a monosaccharide and of, at least, a carbohydrate, andeventually, other excipients as lubricants, aggregate, sweetening, tastecorrectors (flavors) and casually, disaggregating agents used in themanufacture of pills and tablets for sublingual use.

Are considered as advantageous excipients or essential excipients, thoseexcipients used in quantity of at least 60% in weight in relation to thetotal weight of the composition, the carbohydrates as cellulose powder,microcrystalline cellulose or sodium carboxy-methylcellulose, lactose,corn or potato starch, natural or modified, or mixtures thereof andpolyalcohol derivatives from reduction of monosaccharides as D-mannitol,L-glucitol and especially, D-glucitol or sorbitol, which may also act assweetening agent.

In relation to the other excipients, the lubricants aspolyethyleneglycol, especially polyethylene-glycol 6000 are used inquantities corresponding to 0-5% by weight, the aggregative asmicrocrystalline silica are advantageously being used with weightranging between 0,5 and 5%, the disaggregating agent as polyvinylpyrrolidone generally represents from 5 to 10% by weight. In practice,carbohydrates and derivatives thereof, essentially compose theexcipients of the composition of the present invention.

Due to the sublingual use of the pharmaceutical preparation of thepresent invention, the sweetening and/or the flavors constitute anessential presence and will be chosen by experts of the area, inrelation to the organoleptic characteristics of any of the activeprinciples. The natural sweetening are advantageously being used,including mannitol and sorbitol, which in this case are part of thediluents, the latter being used in quantities corresponding to 3-9%,whereas the synthetic sweetening as sodium saccharine or aspartame areused in quantities of 0. 1-5%.

The flavors incorporated to the composition may also be chosen among theflavors of synthetic or natural oils, encompassing plant, leaf, flower,fruit extracts and combinations thereof, as cinnamon, mentha piperita,anise, cedar leaves, bitter almond, citrus fruits, especially orange andlemon, chamomile and grapefruit. The tropical flavors as vanilla oreucalyptus flavor, and fruit essences, especially apple, pear, peach,raspberry, cherry and grape may be advantageously used.

Generally, the flavors are present in quantities ranging from 0.05% to4% of the total weight of the compound. The preferred flavors are thetropical flavors and those that give mint or fruit taste, particularlyof grape, cherry or citric fruits, especially orange, lemon or mixturesthereof.

According to another aspects thereof, the present invention provides apharmaceutical composition that comprises 10-15% by weight of ketorolacor one of its salts acceptable from pharmaceutical viewpoint, preferablyfrom 60 to 75% of the total weight of the compound of an essentialexcipient, composed of a ternary mixture of lactose/sorbitol/cellulose,in the respective weight percentages (in relation to the total weight ofthe compound) of 30-50%/3-9%/9-17%, preferably of 40-50%/5-8%/12-14%.Preferably, in the referred to essential excipient, the relationlactose/cellulose is of approximately 2.5/1 close to 3.5/1, and sorbitolrepresents 6-8% of the total weight of the compound. The referred topharmaceutical composition is found in dosage units of, for example,tablets containing from 2 to 15 mg, preferably 2.5; 5 or 10 mg ofketorolac or one of its salts acceptable from pharmaceutical viewpoint,preferably tromethamol ketorolac. This type of tablets is especiallyappropriate for sublingual administration.

According to a preferential aspect of the invention, the referred toessential excipient is composed of a mixture of lactose (45-48% byweight) /sorbitol (5-8% by weight)/cellulose (12-15% by weight), whichweight relation lactose/sorbitol/cellulose is of 3±0.5/0.6±0.2/1,eventually in a mixture with other excipients acceptable frompharmaceutical viewpoint.

The essential excipients, composed of the mixturelactose/sorbitol/cellulose in the referred to weight percentages, inrelation to the total weight of the compound is preferably a mixturewith a proportion of approximately 3/0.4-0.7/1, containing ternarymixture forming the essential excipients in the weight percentages, eachone always referring to the total weight of the compound, lactose(30-50%)/sorbitol (3-9%)/cellulose (9-17%).

The referred to composition is particularly indicated for sublingualadministration.

In addition to the essential excipients, lactose/sorbitol/cellulose, thecomposition of the invention may contain other excipients, especiallydisaggregating agents, as polyvinyl pyrrolidone, corn or potato starch,eventually modified, lubricants as magnesium stearate, aggregativeagents, as methylcellulose, sodium carboxymethylcellulose,polyethyleneglycol, silica microcrystalline, colloidal silicon dioxide,magnesium and aluminum silicate, dyers as titanium dioxide, sweeteningand flavors as previously mentioned.

The composition of the present invention may contain excipients thatgive it effervescence during the permanence under the tongue. Theadvantageous excipients of this type of composition are the mixtures ofacids and carbonates, adequately prepared in accordance with the usualtechniques, especially citric or tartaric acid and sodium, potassium ormagnesium carbonate or bicarbonate.

The tablets for sublingual administration of the present invention maybe manufactured in accordance with the classic methods used inpharmaceutical technique, for example, by direct compression, by humidgranulation or using technology of active principle incorporation inmicro-granules, microsphere or micro-emulsions, allowing betterabsorption of the referred to active principle.

The composition of the present invention will be prepared according tomethods of pharmaceutical technique.

In practice, the calculated quantity of tromethamol ketorolac, ofsorbitol, preferably micro-granulated and one aggregative, for example,sodium carboxymethyl-cellulose, will pass through a sieve and mixed for10-15 minutes. To this mixture will be added the calculated quantity oflactose, cellulose, preferably micronized, of a disaggregate aspolyvinyl pyrrolidone or crospovidone, for example, Polyplasdone XL, ofa ligand as colloidal silicon, for example, Syloid 244, of a flavor anda sweetening, making all these excipients pass through a sieve of 30mesh and mixing everything for further 10-15 minutes. To the mixturethus obtained will be added the calculated quantity of a lubricant, forexample, magnesium stearate or polyethyleneglycol, mixing for someminutes and making the compression of the mixture with appropriatepunctures.

The composition of the present invention, after administration of a doseof 10 mg, enables the hematic rates of ketorolac to be rapidly reached,thus ensuring rapid analgesic or anti-inflammatory action.

The bioavailability after the sublingual administration of a single doseof 10 mg of tromethamol ketorolac was compared with the same single doseof the active principle in conventional oral tablets, in a study withtwelve healthy male volunteers recruited after the respectiveinformation on the nature and characteristics of the active principlesand also on the scope of the study.

The referred to study, composed of four treatment periods, was carriedout according to a crossed and randomized scheme.

All individuals received the pre-established dose of the activeprinciple in the form of conventional oral tablets, in the form ofsublingual tablets, by endovenous and intramuscular via, within awashout period of at least seven days after the first treatment and eachsubsequent treatment, according to a pre-established list ofrandomization. The sublingual tablets were placed under the tongue incorrespondence with the venous plexus, until its complete dissolution,whereas the conventional oral tablets were swallowed unbroken with 150ml of mineral water. Five ml of venous blood were collected in theperiods 0-5-10-20-40 minutes, 1-2-4-8 and 24 hours after the treatment.Table I shows the average plasmatic rates measured after the singledoses mentioned. TABLE I 5 10 20 40 1 2 4 8 24 0 minutes minutes minutesminutes hour hours hours hours hours E.V. 0 315.83 ± 2858.89 ± 1096.58 ±794.31 ± 637.20 ± 504.58 ± 332.41 ± 156.80 ± 16.21 ± 136.09 680.35376.46 274.46 243.46 228.98 177.30 83.02 18.04 I.M. 0 5.70 ± 119.09 ±245.20 ± 543.08 ± 720.04 ± 448.85 ± 323.04 ± 193.88 ± 25.63 ± 10.3956.83 115.17 316.31 201.80 117.88 103.29 63.74 19.82 Conventional 0 043.73 ± 227.15 ± 660.69 ± 730.60 ± 480.28 ± 317.03 ± 161.04 ± 26.29 ±Tablet 42.88 73.17 303.43 235.35 232.68 190.96 87.83 22.94 Sublingual 043.28 ± 205.26 ± 736.30 ± 776.26 ± 626.88 ± 429.04 ± 305.71 ± 158.35 ±25.41 ± Tablet 31.81 95.16 275.13 287.80 260.98 212.33 182.59 97.7025.46

In above table, exactly in the first minutes after the sublingualadministration, can be observed a tendency for obtaining hematic rateshigher in relation to those obtained after administration of the samedose by oral or intramuscular via, whereas the other plasmatic rates canbe easily overcome.

Table II shows the data referring to the several pharmacokineticparameters (average±standard deviation) referring to sublingual,conventional oral, endovenous and intramuscular administration oftromethanol ketorolac. Especially the AUC_(0-t) informed in the Table,i.e., the area under the time curve 0 up to time T (in this case, athour 24), its logarithm AUC_(0-inf) (in ng/ml/h) i.e., the area underthe curve according to the formulaAUC _(o-inf) =AUC _(0-t) +Ct/b

in which C_(t) is the plasmatic concentration (in ng/ml) estimated attime T (in this case, at hour 24) and b is the slope of the curve of thewashout phase, being its logarithm, the C_(max) (in ng/ml), i.e., thepeak of maximum concentration, its logarithm and the T_(max), i.e., thetime (in hours) in which the maximum plasmatic concentration peak iscompared. TABLE II PHARMACO- KINETIC PARAM- Sublingual ConventionalETERS Tablets Tablets E.V. I.M. AUC _(0-t) 237972.81 ± 233989.13 ±260432.85 ± 260002.03 ± (ng/ml/h) 141094.58 118781.73 141307.54 96077.99AUC _(0-inf) 258205.10 ± 263791.13 ± 281323.89 ± 278349.95 ± (ng/ml/h)143740.06 124504.49 140122.03 92737.20 Log 5.30 ± 5.31 ± 5.36 ± 5.38 ±AUC _(0-t) 0.28 0.24 0.22 0.22 Log 5.34 ± 5.37 ± 5.40 ± 5.41 ± AUC_(0-inf) 0.27 0.24 0.21 0.19 C_(max) 991.47 ± 871.28 ± 2858.89 ± 835.31± (ng/ml) 219.40 236.90 680.35 196.13 Log C_(max) 2.99 ± 2.92 ± 3.45 ±2.91 ± 0.10 0.13 0.10 0.11 T_(max) 33.33 ± 53.33 ± 10 51.67 ± (min)13.03 9.85 — 10.30

From the statistic analyses made from all pharmacokinetic parameters,using the analysis of variance (ANOVA) and the test of Bonferroni, andalso only on the T_(max) parameter, the tests for the data in pairs ofWilcoxon, did not result in significant differences in the treatmentswith reference to logAUC_(o-inf)f, either in ANOVA test or in Bonferronitest, while a significant difference can be observed between theendovenous treatment and the other ways of administration with referenceto logC_(Max). With reference to T_(max) parameter, it was observed thateither in ANOVA test or in Bonferroni and Wilcoxon tests, there is asignificant difference between the treatment by sublingual via and thoseby conventional oral or intramuscular via. It was especially evidencedthat the sublingual treatment presents a T_(max) significantly shorterin relation to the conventional oral or intramuscular treatment,considered equal between it.

The following examples explain the invention, however, without limitingthe same.

EXAMPLE 1

A mixture of 1.000 kg of tromethamol ketorolac, 0.500 kg ofmicro-granulated sorbitol and 0.200 kg of sodium carboxymethylcelluloseis passed through a sieve of 30 mesh, and after that, mixed for 10minutes. Add to this mixture, 3.375 kg of lactose, 1.125 kg ofmicronized cellulose, 0.150 kg of sodium saccharine, 0.6 kg ofPolyplasdone XL, 0.100 kg of Syloid 244 and 0.250 kg of lemon flavor,previously passed through a sieve of 30 mesh. Slurry the mixture for 10minutes. Add 0.200 kg of magnesium stearate previously passed through asieve of 30 mesh. Slurry the end-mixture for 3 minutes. Promote thecompression in an alternative or rotating compression machine, providedwith punctures with 6 mm diameter. Thus, 100,000 tablets will beobtained with a weight of 75 mg each, with a formulation showing thefollowing composition: Tromethamol Ketorolac 10.00 mg Lactose 33.75 mgSorbitol 5.00 mg Micronized Cellulose 11.25 mg SodiumCarboxymethylcellulose 2.00 mg Sodium Saccharine 1.50 mg Polyplasdone XL6.00 mg Syloid 244 1.00 mg Lemon flavor 2.50 mg Magnesium stearate 2.00mg

The tromethamol ketorolac tablets for sublingual administration thusobtained, contain 13.33% of active principle and 66.67% of essentialexcipients, among which lactose represents 45% of the total compound,sorbitol representing 6.67% of the total compound and celluloserepresenting 15% of the total compound, being the proportion oflactose/sorbitol/cellulose of 3/0.44/1.

EXAMPLE 2

Carrying out the same operation described in Example 1 above, with 1.000kg of tromethamol ketorolac, 4.500 kg of Cellactose, composed of amixture containing 75% of lactose and 15% of cellulose, 0.500 kg ofmicro-granulated sorbitol, 0.200 kg of sodium carboxymethyl-cellulose,0.600 kg of polyvinyl pyrrolidone (Collidon Cl BASF), 0.250 kg of lemonflavor (15203-71/MD-Givaudan), 0.100 kg of microcrystalline silica(Syloid 244), 0.200 kg of magnesium stearate and 0.150 kg of sodiumsaccharine 100,000 tablets will be prepared with a weight of 75 mg each,presenting the following composition: Tromethamol Ketorolac 10.00 mgLactose 33.75 mg Microcrystalline Cellulose 11.25 mg MicrogranulatedSorbitol 5.00 mg Polyvinyl pyrrolidone 6.00 mg SodiumCarboxymethylcellulose 2.00 mg Lemon flavor 2.50 mg Sodium Saccharine1.50 mg Magnesium stearate 2.00 mg Microcrystalline Silica 1.00 mg

The tromethamol ketorolac tablets for sublingual administration thusobtained contain 13.33% of active principle and 66.67% of essentialexcipients, among which lactose represents 45% of the total compound,sorbitol representing 6.67% of the total compound and celluloserepresenting 15% of the total compound, being 3/0.44/1 the respectiveproportion of lactose/sorbitol/cellulose.

1. PHARMACEUTICAL COMPOSITION BASED ON KETOROLAC OR ONE OF ITS SALTSPHARMACEUTICALLY ACCEPTABLE, characterized by the use of ketorolac orone to its salts acceptable from pharmaceutical viewpoint forpreparation of pharmaceutical compositions for sublingualadministration, destined to accelerate the pharmacological response toketorolac, without making use of injectable via.
 2. PHARMACEUTICALCOMPOSITION, according to claim 1, characterized for its sublingual use,encompassing as one of its active principles, from 10 to 15% by weightof ketorolac or one of its salts acceptable from the pharmaceuticalviewpoint, constituting, at lest, 60% in relation to the total weight ofthe excipients, of a diluent composed by a polyalcohol derivative fromreduction of a monosaccharide and, at least, a carbohydrate. 3.PHARMACEUTICAL COMPOSITION, according to claim 1 or 2, characterized forconsisting from 10 to 15% by weight of ketocolac or one of its saltsacceptable from pharmaceutical viewpoint and, at least, 60% of essentialexcipients composed of a mixture of lactose/sorbitol/cellulose with therespective weight percentages of 30-50%/3-9%/9/17%.
 4. PHARMACEUTICALCOMPOSITION, according to claim 3 above, characterized by the fact thatthe referred to essential excipient represents 60-75% of its totalweight.
 5. PHARMACEUTICAL COMPOSITION, according to one of the claims 3or 4 above, characterized by the fact that the referred to essentialexcipient is composed of a mixture of lactose (45-48%)/sorbitol (6-8%)/cellulose (12-15%).
 6. PHARMACEUTICAL COMPOSITION, according to one ofthe claims 3 to 5, characterized by the fact that the mixturelactose/cellulose of the referred to essential excipient, is shown inthe proportion lactose/cellulose of approximately 2.5/1 up toapproximately 3.5/1, and sorbitol represents 6-8% of the total weight ofthe compound.
 7. PHARMACEUTICAL COMPOSITION, according to one of theclaims 3 to 6, characterized by the fact that in the referred toessential excipient, the proportion lactose/sorbitol/cellulose is ofapproximately 3±0.5/0.6±0.2/1.
 8. PHARMACEUTICAL COMPOSITION, accordingto one of the claims 3 to 7, characterized by the fact that in thereferred to essential excipient, the proportionlactose/sorbitol/cellulose is of approximately 3/0.4-0.7/1. 9.PHARMACEUTICAL COMPOSITION, according to one of the claims 3 to 8,characterized by the fact that the referred to essential excipient is amixture of excipients acceptable from pharmaceutical viewpoint. 10.PHARMACEUTICAL COMPOSITION, according to one of the claims 3 to 9,characterized by the fact that the same contains from 2 to 15 mg ofketorolac or one of its salts acceptable from pharmaceutical viewpoint.11. PHARMACEUTICAL COMPOSITION according to claim 10, characterized bythe fact that the referred to salt acceptable from pharmaceuticalviewpoint is tromethamol salt.
 12. PHARMACEUTICAL COMPOSITION, accordingto one of the claim 10 or 11, characterized by the fact that the saidcomposition contains 2.5, 5 or 10 mg of tromethamol ketorolac. 13.PHARMACEUTICAL COMPOSITION, in the sublingual form, according to claim1, characterized for being formulated to accelarate the pharmacologicalresponse to ketorolac, in the form of tablets for sublingualadministration, containing from 2 to 15 mg of ketorolac or one of itssalts acceptable from pharmaceutical viewpoint, mixed with apharmaceutical excipient composed of, at least, 60% of diluents composedof a polyalcohol derivative from reduction of a monosaccharide and, atleast, one carbohydrate, in relation to the total weight of theexcipients.
 14. PHARMACEUTICAL COMPOSITION, according to claim 13,characterized by the fact that the said composition consists of at least60% of an essential excipient composed of a ternary mixture oflactose/sorbitol/cellulose in the respective percentages in weight of30-50%/3-9%/9-17%.
 15. PHARMACEUTICAL COMPOSITION, according to one ofclaims 13 or 14, characterized by the fact that in the referred toessential excipient, the proportion lactose/sorbitol/cellulose is ofapproximately 3±0.5/0.6±0.2/1.
 16. PHARMACEUTICAL COMPOSITION, accordingto one of claims 15 to 17, characterized by the fact that the referredto pharmacological response to ketorolac is the rapid induction ofanalgesia.
 17. Use of ketorolac or one of its salts acceptable frompharmaceutical viewpoint, characterized by the fact of being for thepreparation of pharmaceutical compositions for sublingualadministration, destined to accelerate the pharmacological response toketorolac without making use of the injectable via.
 18. Use, accordingto claim 17, characterized by the fact that this pharmacologicalresponse is the analgesic response to ketorolac.